Sensory organs are essential for organisms to assess their environment. Our long- term goals are to understand the roles that non-neuronal glial-like cells play in the function and development of these organs, using the amphid sensory organ of the nematode C. elegans as a model. In multicellular animals, sensory structures are generally composed of both neurons and non-neuronal cells such as specialized glia. Loss of sensory structure function in humans due to disease, injury, or genetic defects has devastating effects not only on an individual's ability to interact with the environment, but also on physical and psychological well being. How sensory structures are assembled from neurons and glia during animal development is largely unknown. Furthermore, the roles played by non-neuronal cells in regulating the functions of sensory neurons are poorly understood. The amphid sensory organ of the nematode C. elegans is an excellent structure in which to study neuron-glia interactions during sensory organ development and function. The amphid is composed of 12 neurons, each with well-defined sensory roles, and two glial-like cells. Amphid architecture and molecular biology are remarkably similar to those of sensory organs in Drosophila and mammals. Furthermore, genetics and molecular biology are generally facile in C. elegans, allowing for discovery of conserved genes affecting amphid development and function. To understand the roles of glial cells in amphid sensory organ function we undertook a cell ablation approach in which one or both glial cells associated with the organ were removed at various times during the animals' life. Our results show that glia are absolutely essential for amphid sensory organ function. Specifically, we demonstrated that glia continuously regulate the shape of sensory endings of some neurons, but can also affect neuronal function without perturbing structure. Furthermore, these studies show that glia continuously produce (and secrete) proteins essential for sensory neurons to transduce environmental stimuli. From a microarray study, we identified 59 secreted/membrane proteins enriched in amphid glia. Here we propose to continue these studies by exploring two proteins in detail, FIG-1, and KCC-2. Both proteins are expressed specifically only in glia, and mutations in these proteins block sensory neuron function without any morphological alterations in either the neurons or the glia. We propose to: (1) Characterize the cell biology and function of FIG-1 to determine how it regulates neuronal activity. (2) Characterize the function of the KCl transporter KCC-2 in regulating neuronal activity. (3) Identify additional glial genes required for the function of C. elegans amphid sensory neurons. Together, these studies should provide important insight into how sensory neuron function is regulated by their associated non-neuronal glial cells. PUBLIC HEALTH RELEVANCE: Sensory organs are important for interactions of humans with their environment, and defects in sensory organ function have debilitating effects on quality of life. Little is known about how non-neuronal cells of these organs promote organ function. Our studies will provide insight into sensory organ function, and delineate targets that might be used to develop treatments for persons with defects in sensory organ function.